Non-Hodgkin Lymphoma

Chronic lymphocytic leukemia/small lymphocytic lymphoma

CLL/SLL is a malignancy of small, round, B lymphocytes involving peripheral blood, bone marrow, and lymph nodes. The term "SLL" is reserved for cases in which there are no circulating malignant lymphocytes. SLL generally presents with lymph node and splenic involvement. Involvement of the bone marrow and peripheral blood may develop later in the course of disease. At the time of presentation, patients may be asymptomatic, complain of only fatigue, or have symptoms related to cytopenias (including autoimmune hemolytic anemia, lymphadenopathy, or splenomegaly).

The immunophenotype helps to distinguish CLL/SLL from other B-cell leukemias/lymphomas, including mantle cell and leukemic forms of follicular lymphoma. Typically, the malignant lymphocytes stain weakly with surface immunoglobulin, CD20, CD22, and CD79b; they are CD5+, CD23+, and FMC7–. Cytogenetic abnormalities are detected in the majority of cases when fluorescence in situ hybridization (FISH) analysis is used. Trisomy 12, deletions at 13q14, and deletions at 11q22-23 are common. Many molecular markers of prognosis have been studied in CLL, including Zap-70, but their value in SLL is unknown.

Given the relatively small numbers of patients with SLL, they have generally been included in clinical trials of "indolent lymphoma." Conventional alkylator-based regimens with rituximab(Drug information on rituximab) as well as purine analogues and combinations including the recently approved agent bendamustine have been used when patients become symptomatic. Anthracyclines have not been shown to benefit patients with CLL/SLL. When compared with follicular lymphoma, CLL/SLL is less likely to respond to rituximab as a single agent. Alemtuzumab(Drug information on alemtuzumab) (Campath), a potent therapy for CLL, is less effective in treating nodal disease than peripheral blood and bone marrow involvement. SCT, both autologous and allogeneic, has been studied in selected patient populations but should be reserved for relapsed young patients with a good performance status.

Splenic marginal zone lymphoma

Splenic marginal zone lymphoma (SMZL) is a rare disorder comprising less than 1% of NHLs. Clinically, this lymphoma most often presents as splenomegaly with splenic hilar node involvement but without peripheral adenopathy. The bone marrow is commonly involved, and malignant villous lymphocytes may be detected in the peripheral blood. Cytopenias are a common presenting feature, often related to hypersplenism and less frequently to an autoimmune process or marrow replacement. Sometimes confused with CLL or MCL, SMZL may be distinguished by its immunophenotype. Typically, cells are CD20+, CD79a+, CD5–, CD10–, CD23–, and CD43–. Staining for cyclin D1 is negative, excluding MCL. The absence of CD103 helps to exclude hairy cell leukemia. Complex karyotypes are common. The clinical course is indolent. Cytopenias may respond to splenectomy with long-lasting remissions. High response rates have been reported with rituximab, and maintenance appears to delay relapse. Transformation to more aggressive histologies may occur. Fludarabine alone or with rituximab appears to be more effective than alkylators which are relatively ineffective in this disease but may be associated with significant toxicity.

Nodal marginal zone lymphoma

Nodal marginal zone lymphoma (NMZL) is a primary nodal B-cell disorder that resembles lymph nodes involved by marginal zone lymphomas of extranodal or splenic origin without extranodal or splenic involvement. Lymphadenopathy (either localized or generalized) is the presenting complaint in most cases. Extranodal lymphoma may be uncovered in the evaluation of many cases of suspected NMZL. The clinical course is usually indolent, similar to that of other marginal zone lymphomas.

Extranodal marginal zone B-cell lymphoma of MALT type

MALT lymphomas comprise only 7% to 8% of B-cell lymphomas but nearly 50% of all gastric lymphomas. Although the GI tract is most often involved, other common sites include the lungs, head and neck, ocular adnexae, skin, thyroid, and breasts. There often is an associated history of autoimmune disorders, such as Sjögren syndrome or Hashimoto thyroiditis or chronic inflammatory processes secondary to infectious agents (Helicobacter pylori, Borrelia burgdorferi, or Chlamydophila psittaci). A form of MALT involving the small bowel (immunoproliferative small intestinal disease, previously known as α-heavy chain disease) has been associated with Campylobacter jejuni. The majority of patients present with stage I or II disease. The frequency of bone marrow involvement appears to differ depending on the primary site of involvement. Multiple extranodal sites may be involved at the time of presentation. Transformation to a high-grade lymphoma may occur in approximately 8% of cases.

The malignant lymphocytes of MALT lymphoma are typically CD20+, CD79a+, CD5–, CD10–, and CD23–. The t(11;18)(q21;q21) is characteristic of MALT lymphomas, particularly those involving the stomach or lungs. The translocation creates a fusion between the MALT-1 gene, which is an essential regulator of bcl-10–mediated NF (nuclear factor)-kB signaling, and the API2 gene, which inhibits apoptosis. This genetic abnormality is a marker of MALT lymphomas that do not respond to antibiotic therapy for H pylori infection, are associated with a more advanced stage, and do not transform into more aggressive NMZLs, SMZLs nodal or splenic MZLs or other types of lymphoma. Additional characteristic translocations have been discovered (Table 1), but their clinical significance is uncertain at this time.

Treatment of H pylori infection with triple therapy (eg, omeprazole [Prilosec], metronidazole, and clarithromycin [Biaxin]) results in regression in the majority of early lesions. However, tumors invading beyond the submucosa and lesions with t(11;18) are associated with a failure to respond to H pylori eradication, deep penetration, and distant spread.

Localized MALT gastric lymphoma that does not respond to antibiotics may be cured with local irradiation, with a field including the stomach and perigastric lymph nodes. This treatment is safe, extremely effective, and preserves the stomach. A single-institution experience reported a 96% complete response rate and a 90% freedom-from-treatment-failure rate, at a median follow-up of 4 years. If local irradiation fails, chemotherapy or rituximab, and in some instances surgery, can be used. Alkylator-based therapy or purine analogues have been used with success for persistent or disseminated disease. The typical dose of radiotherapy is 30 Gy in 20 fractions directed to the stomach and perigastric lymph nodes. Localized nongastric MALT lymphomas also respond well to local radiotherapy.

Lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia

Lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia is a disorder of small B lymphocytes; plasmacytoid lymphocytes; and plasma cells, typically involving the bone marrow, lymph nodes, and spleen. It is usually associated with a serum monoclonal protein (usually IgM) with associated hyperviscosity or cryoglobulinemia. The clinical presentation is usually related to hyperviscosity with visual symptoms, stroke, or congestive heart failure. Peripheral neuropathies occur in approximately 10% of patients related to reactivity of IgM with myelin-associated glycoprotein or gangliosides. An association with HCV infection has been demonstrated. Characteristically, the immunophenotypic analysis reveals surface and cytoplasmic immunoglobulin, usually IgM type, and B-cell–associated antigens (such as CD19, CD20, CD22, and CD79a). The malignant cells are CD5–, CD10–, and CD23–.

The clinical course is generally indolent. Asymptomatic patients may be observed. Plasmapheresis may be appropriate first therapy for those who present with hyperviscosity. The clinical status of the patient, not the level of the protein, determines when treatment is initiated. Choice of therapy depends on many individual factors, including age, comorbidities, and the particular indication for therapy. Rituximab and nucleoside analogues (cladribine and fludarabine) as well as the traditional oral alkylators have shown efficacy, whereas anthracyclines are not beneficial. Rituximab monotherapy may be associated with a rapid rise in IgM levels associated with increased serum viscosity requiring plasmapheresis. Combinations of these agents are also under study. Bortezomib(Drug information on bortezomib), lenalidomide, and alemtuzumab have shown activity in Waldenström's macroglobulinemia. SCT, both autologous and allogeneic, is being investigated in younger patients with relapsed or refractory disease.